Disease-related changes may mask extracellular matrix ligand availability to transplanted cells, impairing post-attachment events and leading, in turn, to cell death or inability of the cells to differentiate. In addition, disease-related changes in the extracellular matrix can promote cell death, leading to the clinical situation in which cell transplantation is contemplated.
One of the conditions in which cell transplantation may be useful is age-related macular degeneration. (In addition, other conditions affecting the macula, such as retinitis pigmentosa and Stargardt disease, may benefit from cell-based therapy.) The macula lutea is an area of the retina that is about 5000 μm in diameter. The center of the macula, the fovea, contains specialized photoreceptors and provides high acuity vision necessary for reading, driving, and recognizing faces. In order for light-sensing photoreceptors to function properly, they must be in intimate contact with a cell layer called the retinal pigment epithelium (RPE). The photoreceptors and RPE exchange nutrients and other materials. The choroid is a vascular layer of the eye wall interposed between the sclera and RPE, and its capillaries, termed the choriocapillaris, provide the blood supply to the RPE and photoreceptors. The RPE is separated from the choriocapillaris by a thin layer of collagenous tissue called Bruch's membrane.
Age-related macular degeneration (AMD) is the most important cause of new cases of blindness in patients older than 55 years of age in the industrialized world. RPE cells may be one of the targets of the pathological processes that cause AMD. Approximately 10% of patients with AMD lose central vision. Among the ˜75% of AMD patients with central visual loss, abnormal blood vessels, termed choroidal new vessels (CNVs), grow from the choriocapillaris and leak fluid and blood under the RPE and macula (exudative or “wet” AMD), which causes visual loss. The stimulus for CNV growth in AMD is complex, and the biochemical pathways are now being identified. One critical element is vascular endothelial growth factor (VEGF), which is involved in CNV growth and leakage. Among ˜25% of AMD patients with severe central visual loss, the RPE and foveal photoreceptors die in the absence of CNVs (atrophic or “dry” AMD, also termed geographic atrophy (GA)). No visually beneficial treatment exits for ˜60-75% of AMD patients.
Existing therapy has significant limitations. Antioxidants, for example, do not seem to be effective in the prevention of early AMD (i.e., drusen, retinal pigmentary changes). The Age-Related Eye Disease Study (AREDS) did not show a statistically significant benefit of the AREDS vitamin and mineral formulation for either the development of new geographic atrophy or for involvement of the fovea in eyes with pre-existing geographic atrophy.
Pharmacological therapies (e.g., AVASTIN® and LUCENTIS®, both of which block the action of VEGF) that are pathway-based have provided the best treatment results for AMD patients that have ever been reported. Nonetheless, a need for improved therapy remains. Although LUCENTIS® treatment is associated with moderate visual improvement in 25-40% of patients according to the results of two randomized studies, the remaining 60-75% of patients are in urgent need of an alternative approach. Also, these medications currently are administered via repeated intravitreal injection, which entails some risk and inconvenience for the patient. Further, pharmacological therapy generally involves administration of a finite number of compounds and usually involves fluctuations in drug levels above and below the desired level.
Accordingly, novel methods and compositions are desired which would address these drawbacks of currently accepted treatment of AMD.